Randomized, double-blinded phase II study of ketoconazole (keto), hydrocortisone (HC), and anti-PSMA antibody J591 labeled with <sup>177</sup>Lu or <sup>111</sup>In in patients (pts) with high-risk non-metastatic (met) castration-resistant prostate cancer (M0 CRPC).
Authors: Scott T. Tagawa, Charlene Thomas, Nabil Adra, Yousef Zakharia, George Philips, David I. Quinn, Neeraj Agarwal, Luke T. Nordquist, Elizabeth Marie Wulff-Burchfield, Leonard Joseph Appleman, Edwin Melencio Posadas, Paul J. Christos, Karla V. Ballman, David M. Nanus, Joseph Osborne
Journal: Journal of Clinical Oncology (2023)

LBA21 Background: Up to 1/3 of pts develop biochemical relapse following primary therapy. Many are not cured with salvage local therapy, likely because of undetectable distant disease. PSMA is expressed on most PC and can be targeted by radiolabeled J591. 177 Lu is a predominantly β-emitting radionuclide and also has γ emission which allows imaging. 111 In is predominantly a γ emitter, also with some auger emission for therapy. Hormonal therapy is effective and may increase PSMA expression and radiosensitize. In this DOD-funded study initiated in the pre-PSMA PET and AR signaling inhibitor era, we hypothesized that 177 Lu prolongs 18-month (mo) met-free survival (MFS) more than 111 In in pts with high risk, M0 CRPC when targeting PSMA via J591 in combo with keto and HC. Methods: Pts with high-risk M0 CRPC defined by PSA DT &lt; 8 mo and/or absolute PSA &gt; 20 ng/mL and serum testosterone &lt; 50 ng/mL with no evidence of metastatic disease on CT/MRI and bone scan were eligible. Treatment included a minimum 4 week lead-in with keto 400 mg TID and HC 20 mg AM, 10 mg PM (both of which could be continued until unacceptable toxicity or development of mets) and a single infusion of J591 with 2:1 randomization to 177 Lu (70 mCi/m 2 ) or 111 In (5 mCi) in double-blinded fashion. The final version of the protocol was designed to randomize 55 pts for 80% power to detect a difference in 18-mo MFS with one-sided alpha of 10%. Secondary endpoints include median MFS, PSA response, overall survival, and toxicity. Results: 55 pts with median age 68 (range 52 - 88), 75% prostatectomy, 23% primary radiation, 2% primary ADT; 19% local salvage therapy. Median PSA doubling time 3 mo (range 0.87 – 7.85), median baseline PSA 8.0 (range 1-78). In intent to treat analysis (5 without imaging and 4 lost to follow up by 18 mo), 50% developed mets by 18 mo with 177 Lu vs 76% with 111 In (p=0.066). Median MFS was 23.8 mo vs 20.8 mo, and biochemical PFS was 18.67 vs 8.87 mo, favoring 177 Lu in analyses censoring start of new treatment. Confirmed &gt;50% PSA decline occurred in 82% with 177 Lu and 71% with 111 In. Grade &gt;3 heme AEs were more common with 177 Lu vs 111 In, including neutropenia (57% vs 11%, with 1 febrile neutropenia) and thrombocytopenia (77% vs 11%, with 25% vs 6% platelet transfusions), whereas Gr &gt;3 non-heme AEs were less common with 177 Lu vs 111 In, including abdominal pain (0 vs 11%), ALT increase (3.3% vs 22%), and diarrhea (0 vs 22%). Conclusions: Anti-PSMA mAb J591 with keto/HC when radiolabeled with 177 Lu leads to improved 18-month met-free survival vs 111 In. Most pts had significant PSA decline with either version of radiolabeled J591 with keto/HC. Hematologic toxicity is more common with 177 Lu. This supports the development of anti-PSMA radioimmunotherapy for low volume advanced PC, though the optimal radionuclide and targeting agent is unknown. Clinical trial information: NCT00859781 .